Engineering an End to Aging

Most of what is marketed as “life extension” products today are quite useless. None of them will actually increase your life span. Usually, they’re snake oil. At best, they improve external appearance without actually extending life. We deserve better, and we’ll need it if we want to live longer than the typical three score and ten years.

The first thing to realize is that nature doesn’t specifically want us to die. There is no “death gene.” For any species in any environmental context, there is an ideal life span from an adaptive point of view — an evolutionary optima. One evolutionary strategy includes species that reproduce quickly and die off fast. Another includes species that reproduce slowly and live for a long time. Call it quality versus quantity. Thankfully for humans, we’re squarely in the quality column, but many would agree that 80 to 90 years is not enough.

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We perish not because of some internal clock that says, “Time to die now!,” but because of a lack of attention and self-healing — mere neglect. Once we’ve reproduced a few times, in the eyes of nature, our usefulness has run its course. We are cast aside, onto a pile of skeletons 600 million years deep. This is unacceptable, and we need to find a new way, but since nature isn’t actively working against us — just neglecting us — the challenge is surmountable.

LONGEVITY IN NATURE

First, let’s look to nature for inspiration. Are there any animals with extraordinarily long life or regenerative capacities? Absolutely.

There is one animal that scientists believe is immortal — the lowly hydra, a simple, microscopic freshwater animal, shaped something like a tiny squid. Apparently, the challenges of indefinite tissue regeneration are simple enough for such a small organism that nature has solved them. American biologist Daniel M. Marinez did a study of mortality in three colonies of hydra for four years straight, and barely any of them died.

Death rates were random, uncorrelated with age. This means they weren’t displaying senescence (aging), and died from other causes. In almost all other known species, death rates increase with age. Not in hydra. They die from getting eaten, or infected by a virus, or squished, but not from aging. There could be a thousand-year-old hydra out there, maybe in a small lake right in your neighborhood. We don’t know, because there is no way of telling their age by looking at them!

Planarians — those odd animals that look like a slug squished in a microscope slide — are another organism that scientists suspect may be immortal. No detailed studies have been conducted yet. In many cases, if you cut a planarian in half, it becomes two planarians. These live as long as one born by conventional means. If you kept cutting a planarian in half, it might never die, because each piece would go on living.

What about more-complex animals? There are our friends in the order Testudines: turtles, tortoises, and terrapins. Scientists have examined the internal organs of young and old turtles and found that they look exactly the same. Something in a turtle’s physiology prevents these organs from breaking down. An article in Discover magazine asked, “Can Turtles Live Forever,” and came to the conclusion that it’s entirely possible. Like hydra, turtles experience no increase in mortality rates and no decrease in reproductive rates as they grow older. There are turtles 150 years old that exhibit no signs of aging. Harriet the Turtle, a pet of Charles Darwin’s, was born in 1830 and died only in 2006. It seems turtles can die from disease, injury, or predation, but not aging. This quality is called “negligible senescence.” Sign me up.

From these animal examples, we see it would be premature to state that negligible senescence is biologically impossible, as is frequently assumed. Nature seems to be uninterested in our quaint notion that all organisms must age. The question is — how can we make this work for humans? The oldest person who ever lived, Jeanne Louise Calment, kicked the bucket at the age of 122 1/2. Can we push that boundary?

ENGINEERING NEGLIGIBLE SENESCENCE

Enter Dr. Aubrey de Grey, a biogerontologist from the UK, and his “strategies for engineered negligible senescence” (SENS) plan. Instead of exclusively studying the complex biochemical processes of aging in detail, as in gerontology, or ameliorating the worst symptoms of age-related decline, as in geriatrics, de Grey and his supporters advocate an “engineering approach” to aging that asks, what are the main categories of age-related biochemical damage, and how can we fix them? The idea is not to eliminate the sources of age-related damage, but to fix the damage fast enough so it doesn’t accumulate and cause health problems. This is far easier than deciphering all the intricacies of the biochemistry of aging.

Although some tentative engineering approaches to aging had been proposed before, it was de Grey who really fleshed it out, popularized it, and made it respectable. It’s no wonder that he has already raised $10 million in funding for his organization, the Methuselah Foundation.

As de Grey points out, gerontologists have discovered seven biochemical causes of aging. The last cause was discovered in 1981, and considering how immensely far our knowledge of biology has come since that time, it seems quite likely that these seven causes are all of them. De Grey calls these causes of aging the “Seven Deadly Things.” They are: (1) cell loss, (2) death resistant cells, (3) nuclear DNA mutations, (4) mitochondrial DNA mutations, (5) intracellular junk, (6) extracellular junk, and (7) extracellular crosslinks. That’s it. If we find medicines or therapies that can clean up this damage, we could extend our lifes pans to great lengths and achieve negligible senescence in humans.

A word on a philosophical point of view: many world philosophies and religions teach, or strongly imply, that the body depends on some immaterial animating force, a soul or chi, to give it life. Scientists disagree: the functioning of the body seems entirely rooted in atoms, molecules, and forces between them. As recently as 1907, French philosopher Henri Bergeson wrote about an élan vital, or vital force, that animated all living things and drove their evolution and development. This was closely connected to the idea, common at the time, that organic molecules could not be synthesized by inorganic precursors. Unfortunately for Bergeson and other vitalists, Friedrich Wöhler, the father of biochemistry, had already synthesized urea from inorganic precursors as early as 1828, and scientists were becoming more and more convinced that the same laws of biochemistry that govern inorganic molecules govern organic molecules as well.

Because the laws of chemistry apply to both life and non-life, aging is an entirely chemical, non-mystical process of degradation with specific physical causes. Although it is a matter of preference whether you consider aging a “disease” or not, from the perspective of the body, aging is like a disease — a life-destroying biochemical phenomenon occurring in the body. And like diseases, aging is treatable.

We perish not because of some internal clock that says, “Time to die now!,” but because of a lack of attention and self-healing mere neglect.

It is due to the complexity and the aura of inevitability around aging that people have only recently begun to look at it this way. Some say that aging is something mandated by God, and we have no right to mess with it, but these very same people have used this same argument throughout history to protest against vaccinations, the dissection of cadavers, organ transplants, and numerous other therapies or techniques of extreme medical value. Is it so radical to say that being healthy is a good thing, and that we should use whatever ethical strategies are available to pursue that end?

Aubrey de Grey’s SENS plan is complex and quite thorough. To examine it in full, I suggest looking at the website of the Methuselah Foundation, or getting his recent book, Ending Aging. But I will summarize the basics here.

The first cause of aging is cell loss, or cell atrophy. For most of our lives, our bodies are programmed to replace cells when they die. Our individual cells live much shorter life spans than the body itself: some cells last a few years, others, like skin cells, a few weeks. All of them are constantly regenerated using the body’s supply of stem cells. Over time, the processes of cell replenishment begin to break down. This is what causes muscle atrophy among the old, and the phenomenon especially afflicts the heart and brain, our two most important organs. To fix this problem, two strategies have been proposed: stimulating the division of existing cells, or introducing new cells, possibly including stem cells. Both are under investigation.

The second cause of aging is death resistant cells, cells that overstay their welcome. There are three main types of cells guilty of this offense. The first are visceral fat cells, fat cells that build up around our internal organs. These cause a progressive loss in our body’s ability to respond to nutrients from the stomach. Eventually, it leads to Type 2 Diabetes. The second type of cells is called senescent cells, cells that have lost the ability to reproduce. These stick around, releasing proteins that are dangerous to their neighbors. Thankfully, they primarily aggregate in just one type of tissue, the cartilage between our joints. A third type is a category of immune cells called “memory cytotoxic T cells.” These build up faster than other immune cells and refuse to go away, crowding out the other immune cells and eventually causing disease. There are two approaches to solving these problems: inject something that makes the unwanted cells commit suicide but doesn’t touch other cells, or stimulate the immune system to kill the target cells.

The third cause of aging is mutations in the DNA of the nucleus, the center of every cell. Most of these mutations are entirely harmless, as they only affect a few cells at a time. These cells eventually die and are replaced with unmutated cells. Mutations get dangerous when they lead to malignant cells that self-replicate — otherwise known as cancer. So, finding a cure for a cancer is a subtask of finding a cure for aging. According to de Grey, this is the most difficult part of the strategy, because cancer is constantly evolving to exploit us.

There are several proposed approaches to finding a cure for cancer, but de Grey’s favored strategy is one called “Whole-body Interdiction of Lengthening of Telomeres” (WILT). The Methuselah Foundation’s website calls WILT “a very ambitious but potentially far more comprehensive and long-term approach to combating cancer than anything currently available or in development.” It is based on a vulnerability shared among all cancer cells: their need to renew their telomeres, junk DNA that serves as the ends of chromosomes. Telomeres of a certain length are necessary for a cell to self-replicate. If the telomeres are too short, the cell self-destructs. When cancer hijacks the body’s cells, the cancer cells replicate so rapidly that their telomeres shorten quickly. The cancer cells avoid destruction by using the cell’s protein synthesis machinery to build enzymes — telomerase and ALT — that extend telomeres, and allow endless selfreplication. Previous attempts at cancer cures target these enzymes, but WILT proposes removing the very genes that contain the information necessary to synthesize them.

Removing the genes underlying the synthesis of telomerase will mean that all cancers will self-destruct before becoming a serious problem to their host, effectively curing cancer. This is one of the most ambitious strands of the SENS plan. The challenge of this approach is that removing these genes in all the tissues of the body will mean that the body’s natural cells will have a limited life span, as they will not be capable of lengthening their telomeres. To counteract this will require introducing stem cells with renewed telomeres into the body every decade or so. This has already been demonstrated in mice with cells of the blood and gut. Skin and lungs will be next. When this therapy is used to cure cancer in mice, tremendous resources will be pumped into efforts to develop a therapy that works for humans.

The fourth cause of aging is mutations in the mitochondria, the “power stations” of the cell. Mitochondria have their own DNA, much less than that in the nucleus of the cell, but some of it is essential to synthesizing the proteins that make it up. When the DNA is damaged, the mitochondria break down. Mitochondrial DNA is especially susceptible to damage because of two reasons. The first is that mitochondria, being the site of cellular respiration, are heavily exposed to its by-products — dangerous free radicals. These react with the DNA, causing it to mutate. The second is that mitochondria lack the complex DNA-repair machinery found in the nucleus.

Luckily, although mitochondria are made of thousands of proteins, only 13 of them are synthesized using the genes of the mitochondria itself. The rest are synthesized in the nucleus and imported in. The solution to this problem is to move the thirteen critical genes from the mitochondria to the nucleus of the cell. Evolution has already been doing this without our help for millions of years, and we need to finish the job. This will require using gene therapy to add supplementary genes. Gene therapy is in its early stages, but has been used effectively to replace defective genes with functional ones, helping cure genetic diseases. Research is under way to improve the process and test it with mice.

…aging – besides killing more than 100,000 people per day; it makes us suffer for years or decades before it kills us.

The fifth cause of aging is intracellular junk. Cells synthesize, reconstruct, and deconstruct many thousands of different molecules during the course of their operation. Every once in a while a cell ends up with a molecule so large or unusual that it has trouble breaking it up. If a molecule cannot be broken down by the “incinerator” of the cell, the lysosome, it stays there forever. In cells that don’t divide, this can build up to critical levels. This includes some cells in the heart, the back of the eye, some nerve cells, and white blood cells trapped in the walls of arteries. This can cause diseases, such as Alzheimer’s, Parkinson’s, macular degeneration (the leading cause of acquired blindness), and atherosclerosis. To clean up intracellular junk, the SENS project proposes equipping the lysosome with new enzymes, thereby expanding the range of molecules it can break down, allowing it to digest even very large or unusual molecules.

The sixth cause of aging is extracellular crosslinks, molecular garbage that accumulates outside cells, linking together proteins that otherwise slide smoothly over each other. These can lead to some of the most outwardly visible effects of aging: wrinkles in tissue and the like. Fortunately, these crosslink molecules have chemical structures different than the healthy tissue of the body, so it shouldn’t be too hard to find an enzyme that breaks them down while leaving the rest alone. In fact, just one type of crosslinks, called glucosepane crosslinks, may count for up to 98% of all long-lived extracellular crosslinks in the human body, meaning if we figure out a way to get rid of these, we’ll have almost solved this cause of age-related damage.

The seventh and last known cause of aging is general extracellular junk, the type that just floats around instead of linking together proteins. Most of these junk molecules are called amyloids, and they build up in everyone, but are especially found in the brains of Alzheimer’s patients. The main approach to dealing with this, already being pursued by at least one company, is to stimulate the body’s immune cells to clear out these molecules. There is a strong overlap between treatments for Alzheimer’s and atherosclerosis and anti-aging treatments that address this cause, so there seems to be significant momentum in the right direction.

There may be other causes of aging that emerge after we have solved most of these seven. We’ll just have to wait and see. But if all these seven causes of aging were eliminated, people could live a lot longer — maybe even hundreds of years. That would buy us more time to develop new therapies to address the remaining sources of aging.

It’s hard to imagine why we wouldn’t want to fight the scourge of aging — besides killing more than 100,000 people per day; it makes us suffer for years or decades before it kills us. Everyone is susceptible. Instead of seeing aging as inevitable, why don’t we view it as a disease and search for a cure?

Michael Anissimov is a science writer. He blogs at accelerating future.

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